SLC54 Mitochondrial pyruvate carriers (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

Pyruvate is oxidized to acetyl‐CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. The mitochondrial pyruvate carrier (MPC) is a hetero-oligomer composed of SLC54 family members (MPC1 and MPC2). The MPC is expressed in the inner mitochondrial membrane and involved in the import of pyruvate into mitochondria [1, 5]. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [7, 8]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, specifically inhibit the MPC [3]

SLC54 Mitochondrial pyruvate carriers in GtoPdb v.2023.1

Pyruvate is oxidized to acetyl‐CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. The mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 and MPC2) [1, 5], which form functional hetero-dimers [9, 8]. The MPC is expressed in the inner mitochondrial membrane and involved in the import of pyruvate into mitochondria [1, 5]. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [11, 12]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, inhibit the MPC [3]. Other clinically relevant inhibitors of the MPC complex are lonidamine [7, 8], quinolone antibacterials [6], entacapone and nitrofurantoin [8]

FK506 regulates IP3 evoked Ca2+ release independently of FKBP in endothelial cells

Background and Purpose FK506 and rapamycin are modulators of FK-binding proteins (FKBP) that are used to suppress immune function after organ and hematopoietic stem cell transplantations. The drugs share the unwanted side-effect of evoking hypertension that is associated with reduced endothelial function and nitric oxide production. The underlying mechanisms are not understood. FKBP may regulate IP3 and ryanodine receptors to alter Ca2+ signalling in endothelial cells. Experimental Approach We investigated the effects of FK506 and rapamycin on Ca2+ release via IP3 and ryanodine receptors in large numbers of endothelial cells in intact arteries. Key Results While confirmed to be present, FKBP modulation with rapamycin did not alter IP3-evoked Ca2+ release. Conversely, FK506, which modulates FKBP and additionally blocks calcineurin, increased IP3-evoked Ca2+ release. Inhibition of calcineurin (using okadiac acid or cypermethrin) also increased IP3-evoked Ca2+ release and blocked FK506 effects. Indeed, when calcineurin was inhibited with okadiac acid, FK506 reduced IP3-evoked Ca2+ release. These findings suggest that FKBP does not modulate IP3-evoked Ca2+ release and FK506 increased IP3-evoked Ca2+ release by calcineurin inhibition. FK506 and rapamycin are also unlikely to mediate their effects via RyR. The RyR activator caffeine and ryanodine itself failed to evoke Ca2+ changes suggesting that RyR is not functional in native endothelium. Conclusion and Implications The hypertensive effects of the immunosuppressant drugs FK506 and rapamycin, while mediated by endothelial cells, do not appear to be exerted at documented cellular targets of the drugs on Ca2+ release and altered FKBP binding to IP3 and RyR

The endothelium solves problems that endothelial cells do not know exist

The endothelium is the single layer of cells that lines the entire cardiovascular system and that regulates vascular tone and blood-tissue exchange, recruits blood cells, modulates blood clotting and determines the formation of new blood vessels. To control each function, the endothelium uses a remarkable sensory capability to continuously monitor vanishingly small changes in the concentration of many simultaneously arriving extracellular activators that each provide cues to physiological state. Here, we suggest that the extraordinary sensory capabilities of the endothelium does not come from single cells but from the combined activity of a large number of endothelial cells. Each cell has a limited, but distinctive, sensory capacity and shares information with neighbours so that sensing is distributed among cells. Communication of information among connected cells provides a system-level sensing substantially greater than the capabilities of any single cell and, as a collective, the endothelium solves sensory problems too complex for any single cell

Pressure-dependent regulation of Ca2+ signaling in the vascular endothelium

The endothelium is an interconnected network upon which hemodynamic mechanical forces act to control vascular tone and remodeling in disease. Ca2+ signaling is central to the endothelium's mechanotransduction and networked activity. However, challenges in imaging Ca2+ in large numbers of endothelial cells under conditions that preserve the intact physical configuration of pressurized arteries have limited progress in understanding how pressure-dependent mechanical forces alter networked Ca2+ signaling. We developed a miniature wide-field, gradient-index (GRIN) optical probe designed to fit inside an intact pressurized artery which permitted Ca2+ signals to be imaged with subcellular resolution in a large number (∼200) of naturally-connected endothelial cells at various pressures. Chemical (acetylcholine) activation triggered spatiotemporally-complex, propagating IP3-mediated Ca2+ waves that originated in clusters of cells and progressed from there across the endothelium. Mechanical stimulation of the artery, by increased intraluminal pressure, flattened the endothelial cells and suppressed IP3-mediated Ca2+ signals in all activated cells. By computationally modeling Ca2+ release, endothelial shape changes were shown to alter the geometry of the Ca2+ diffusive environment near IP3 receptor microdomains to limit IP3-mediated Ca2+ signals as pressure increased. Changes in cell shape produce a geometric, microdomain-regulation of IP3-mediated Ca2+ signaling to explain macroscopic pressure-dependent, endothelial-mechanosensing without the need for a conventional mechanoreceptor. The suppression of IP3-mediated Ca2+ signaling may explain the decrease in endothelial activity as pressure increases. GRIN imaging provides a convenient method that provides access to hundreds of endothelial cells in intact arteries in physiological configuration

Chapter 9 Mitochondria Structure and Position in the Local Control of Calcium Signals in Smooth Muscle Cells

Features of Ca2+ signals including the amplitude, duration, frequency and location are encoded by various physiological stimuli. These features of the signals are decoded by cells to selectively activate smooth muscle functions that include contraction and proliferation [1–3]. Central, therefore, to an appreciation of how smooth muscle is controlled is an understanding of the regulation of Ca2+

Genomic Characterisation of an Isolate of Brassica Yellows Virus Associated with Brassica Weed in Tasmania

Brassica yellows virus (BrYV), a tentative species in the genus Polerovirus, of the Solemoviridae family, is a phloem-restricted and aphid-transmitted virus with at least three genotypes (A, B, and C). It has been found across mainland China, South Korea, and Japan. BrYV was previously undescribed in Tasmania, and its genetic variability in the state remains unknown. Here, we describe a near-complete genome sequence of BrYV (genotype A) isolated from Raphanus raphanistrum in Tasmania using next-generation sequencing and sanger sequencing of RT-PCR products. BrYV-Tas (GenBank Accession no. OM469309) possesses a genome of 5516 nucleotides (nt) and shares higher sequence identity (about 90%) with other BrYV isolates. Phylogenetic analyses showed variability in the clustering patterns of the individual genes of BrYV-Tas. Recombination analysis revealed beginning and ending breakpoints at nucleotide positions 1922 to 5234 nt, with the BrYV isolate LC428359 and BrYV isolate KY310572 identified as major and minor parents, respectively. Results of the evolutionary analysis showed that the majority of the codons for each gene are evolving under purifying selection, though a few codons were also detected to have positive selection pressure. Taken together, our findings will facilitate an understanding of the evolutionary dynamics and genetic diversity of BrYV

Optical analogues of the Newton–Schrödinger equation and boson star evolution

Many gravitational phenomena that lie at the core of our understanding of the Universe have not yet been directly observed. An example in this sense is the boson star that has been proposed as an alternative to some compact objects currently interpreted as being black holes. In the weak field limit, these stars are governed by the Newton–Schrodinger equation. Here we present an optical system that, under appropriate conditions, identically reproduces such equation in two dimensions. A rotating boson star is experimentally and numerically modelled by an optical beam propagating through a medium with a positive thermal nonlinearity and is shown to oscillate in time while also stable up to relatively high densities. For higher densities, instabilities lead to an apparent breakup of the star, yet coherence across the whole structure is maintained. These results show that optical analogues can be used to shed new light on inaccessible gravitational objects

Diseases of Pyrethrum in Tasmania: Challenges and Prospects for Management

Pyrethrum (Tanacetum cinerariifolium (Trevir.) Sch. Bip.) is a perennial plant and member of the Asteraceae that is endemic to the Dalmatian region of the former Yugoslavia (36). Pyrethrum is cultivated commercially solely for the production of six closely related esters called pyrethrins. The plant is tufted, slender, and herbaceous, growing to a height of approximately one meter (18). Leaves are alternate and pinnately lobed/narrowly lanceolate to oblong lanceolate. The daisy-like flowers are produced at the termini of stems and consist of a cluster of 40 to 100 bisexual, yellow disk florets encircled by a ring of 18 to 22 pistillate white ray florets atop a moderately convex to subglobose receptacle (Fig. 1; 100). Disk and ray florets both possess 3 to 10 ribbed achenes located between the floret and receptacle. Involucres generally range between 12 and 18 mm in diameter (17,18). Approximately 94% o